Dr. Len's Cancer Blog

Expert perspective, insight and discussion

Vaccines (23 posts)

An article in today’s New England Journal of Medicine reports some interesting and intriguing research that may help some women with a not uncommon pre-cancerous lesion of the vulva called vulvar intraepithelial neoplasia, or VIN.

By using proteins found in the cancer-causing human papilloma virus type 16 (HPV-16), the researchers were able to make a vaccine that actually led to an effective treatment for a small group of women with VIN, resulting in complete disappearance of the lesion in almost half of the women they treated.

You may have heard of HPV infections.These are the viruses that cause cervical cancer.Two of these viruses—types 16 and 18—are responsible for the majority of cervical cancers in the United States.They are also the viruses targeted by currently available vaccines which prevent infection with HPV thus reducing the risk of developing cervical cancer.

It turns out that the same viruses are also related to VIN, especially type 16 which causes over 75% of VIN. (VIN is a superficial lesion on the vulva which can actually last for many years.)

The problem is that the treatments for VIN are sometimes unsatisfactory, and the lesions can recur frequently after treatment.Topical medicines, surgery and laser treatments are commonly used.More recently, an antiviral medicine called imiquimod has been reported to be effective and less irritating.About 1 out of 65 VIN lesions can resolve spontaneously.

And, just like what can happen in the cervix where the HPV infection progresses on to cervical cancer, untreated VIN can become an actual vulvar cancer.Fortunately, this is uncommon.

In this current report, the doctors made a vaccine using cancer-causing proteins from the virus.They treated women with advanced pre-cancerous VIN by giving them the vaccine under the skin of the arm or leg every three weeks for a total of three to four injections.Side effects were tolerable, and frequently included a local reaction at the vaccination site in addition to flu like symptoms, chills and tiredness.

The responses in some of the women were remarkable: At one year, 6 of the 19 patients had a partial response to the vaccine. 9 of the patients (47%) had complete disappearance of the VIN, which lasted for at least another 12 months.As a result, 79% of the women responded to the vaccine.This compares to a complete response rate of 35% for lesions treated with imiquimod, according to the report.

Unfortunately, not all of the women had such positive responses to the vaccine.Two of the participants went on to develop cancer, and one of those women had shown a previous partial response to the vaccine.

The researchers also measured whether the women’s immune systems responded to the vaccine.All of the women in the study did have a response, and those with a complete resolution of their VIN at 3 months after treatment had much stronger responses compared to women who did not have a complete regression.

What’s interesting to me about this research is that it seems to work in a way that is different from what we have seen before.

We are all familiar with the typical types of vaccines, where the vaccine contains a protein from a virus or bacteria that is given to us when we aren’t sick with an infection and then prevents us from getting the same infection at a later date.

Here we have a situation where the woman is already infected with the virus, and her body has either not developed a response to the infection or become “tolerant” to the virus.That’s usually a situation where vaccination doesn’t work.Think of having the flu, then getting the flu vaccine.Basically, it’s too late.

That same theory carries over to the currently available cervical cancer vaccine.If a woman has already become sexually active and infected with HPV, then giving her the preventive vaccine isn’t going to be effective in reducing her risk of cervical cancer.

But, for some reason, in this trial giving a piece of the virus to stimulate the immune system after the infection had set in did work. What I don’t understand is how that happened.It just is not what one would ordinarily expect based on the science.

These doctors weren’t interested in making a prevention vaccine.What they developed, as they report, was a therapeutic vaccine.

Maybe I shouldn’t be so worried about how this happened, and just be glad that in fact it did happen.

The implications of this research are significant.

First, it may mean that this vaccine will be studied further (this was a very small, early stage trial) and eventually be available for wider use in the treatment of women with VIN.

But—perhaps more importantly—it raises the question of whether a similar approach could be used in women who have advanced pre-cancerous lesions in the cervix.

These researchers have actually previously reported studies using the same vaccine in women with either advanced or treated cervical cancer.In one study, they vaccinated women who had cervical cancer that was successfully treated surgically, and were able to induce an immune response to HPV-16 using this vaccine.

As they stated in that article, the results of the study “indicates the potential of this vaccine for the immunotherapy of HPV 16-induced progressive infections, lesions, and malignancies.”

In plain language, if this vaccine is effective in VIN, and it can demonstrate the ability to cause an immune response in women who have already been diagnosed with cervical cancer, then maybe it can also be effective in treating women who have pre-cancerous cervical lesions as well.

I suspect it will be some time before we know the rest of the story as to whether this vaccine is truly effective in treating women with VIN or whether it can improve the treatment for women with pre-cancerous lesions of the cervix.Patience is clearly going to be part of the process.

But if this theory holds up, then this report could be the foundation of a new approach to treating some not-uncommon pre-cancerous diseases.And that is very exciting news indeed.

Two articles and an editorial in the current issue of the Journal of the American Medical Association (JAMA) about the side effects and marketing of the cervical cancer vaccine are probably going to raise questions.They may also fuel the fires of concerns among some groups that have raised thorny political questions about the vaccine, especially as to whether or not this vaccine should be mandatory for young girls.

The primary “scientific” report in JAMA describes the results of a post-marketing surveillance program that monitors the side effects of new vaccines.

In order to monitor reports of subsequent adverse reactions, the CDC and the FDA sponsor an adverse event reporting system called the US Vaccine Adverse Event Reporting System (VAERS).Anyone can submit a report of a suspected vaccine-related adverse event to this system, even if they are not the patient, a family member, a physician or other health care professional.Once the vaccine has been in widespread use for a sufficient period of time, those reports can be evaluated and researchers can determine whether or not there are any unsuspected safety signals, or if certain adverse events occur more frequently than would have been anticipated based on the initial clinical trials.

More than 23 million doses of the cervical cancer vaccine had been distributed in the United States between the date it was approved in June 2006 and December 31, 2008.

During that period of time, the VAERS had received 12,424 reports of adverse events following vaccination with the HPV vaccine.Most of the reports came from the manufacturer, but unfortunately those reports did not have patient information so they could not be verified.Also, many of the reports included multiple adverse reactions in single patients.

The most common reactions were syncope (fainting) in 15% of the reports, followed by dizziness, nausea, headache and reactions at the injection site.

There were 1896 reports of fainting, and 15% of those reports included a fall.Of the people who fell, about 2/3 had a head injury as a result of the fall.

The researchers tried to verify many of the more serious events, but were stymied by the lack of medical information that was available.In addition, a number of the reports of serious events were based on hearsay, where the person who reported the event did not have first hand knowledge of the reaction.

Obviously, the greatest concern is with the reports of 32 deaths that may have been associated with the vaccine.Of those cases where data was available, there were several different causes of death including four that were unexplained.

The authors conclude that the safety profile was in line with what would have been expected from the initial clinical trials of the vaccine.They did point out, however, that there was a higher rate of syncope and blood clots (DVT) than was expected.They also noted that surveillance is continuing.

Syncope after vaccination is not a new problem with vaccinations.The authors note that fainting after a shot is not unusual in young people, especially young women between the ages of 11 and 18. They emphasized the need for patients, families, and health care professionals to follow recommended precautions after giving this vaccine, in order to prevent more serious injury.

The authors also noted that this reporting system is “passive.” That means it relies on people letting the CDC and the FDA know about adverse events.They also think publicity increased the number of adverse events that were reported since there were three times the number of reports for this vaccine compared to the rate seen for all other vaccines combined.

Their conclusion?

“The post licensure safety profile presented here is broadly consistent with safety data from pre-licensure trials.Because VAERS data must be interpreted cautiously and cannot generally be used to infer causal associations between vaccines and (adverse events), post licensure monitoring will continue and identified signals may be evaluated using epidemiologic observational studies.”

So that’s the science.Now for the more controversial part of this report, which calls into question how this vaccine was marketed and what role medical associations may have played into misleading their physician members about the vaccine.

The authors of this article, from the Columbia College of Physicians and Surgeons in New York, refer to “critical and unresolved questions” about the vaccine in terms of how it was marketed, whether the vaccine was being targeted to those young women who need it most, and whether the medical societies were really unbiased in their presentations about the vaccine.

The authors maintain that by marketing this vaccine to prevent cervical cancer as opposed to preventing infection with a virus resulted in the vaccine gaining greater acceptance in the community and among physicians.The authors claim that the public was led to believe that every young girl was at equal risk of getting cervical cancer, as opposed to focusing on young girls at greater risk of getting cervical cancer.Those girls at risk are frequently economically and educationally disadvantaged which results in a lower likelihood that they will follow cervical cancer screening recommendations as they grow into adulthood.

To me, the most disconcerting allegations in this article are leveled at “professional medical associations” (PMAs) which are physician membership organizations that are highly regarded and have a significant nationwide presence.The authors suggest that some of these organizations altered their professional focus and messaging surrounding cervical cancer as a result of corporate funding.They established well-resourced speaker bureaus funded by the manufacturer to provide continuing medical education lectures, including carefully designed scripts and slides.Even potentially controversial or difficult questions had very specific responses crafted as part of these kits.

The authors conclude:

“As marketing of this HPV vaccine demonstrates, pharmaceutical company campaigns can undercut the most cost-effective and appropriate use of new agents to the detriment of adolescent health.By making this vaccine’s target disease cervical cancer, the sexual transmission of HPV was minimized, the threat of cervical cancer to all adolescents maximized, and the subpopulations most at risk practically ignored…Under no circumstances should PMAs administer product-specific speakers’ bureaus, nor should they accept funding that requires them to report activity to the donor.”

These are serious comments. And don’t forget that they appear in JAMA, which is the medical journal published by the American Medical Association, the granddaddy of professional medical associations (although there is no suggestion that the AMA was engaged in any of these activities).

The editorial also discusses the complexity of decision making when it comes to evaluating the risks and benefits of a new medical treatment, such as the cervical cancer vaccine.The writer points out persistent lack of knowledge about the vaccine, such as the impact on cervical cancer rates 20 or 40 years from now, and the fact that more long term studies about the vaccine were needed but have not yet been reported.

The opinion of the editorialist is bound to be the topic of discussion in the medical community:

“The net benefit of the HPV vaccine to a woman is uncertain.Even if persistently infected with HPV, a woman most likely will not develop cancer if she is regularly screened.So rationally she should be willing to accept only a small risk of harmful effects from the vaccine.

“When weighing evidence about risks and benefits, it is also appropriate to ask who takes the risk, and who gets the benefit.Patients and the public logically expect that only medical and scientific evidence is put on the balance. If other matters weigh in, such as profit for a company or financial or professional gains for physicians or groups of physicians, the balance is easily skewed.The balance will also tilt if the adverse events are not calculated correctly.”

So what does the American Cancer Society recommend?

Our guidelines call for routine vaccination of girls ages 11 and 12, and as young as 9.We also recommend the vaccine for women ages 13 through 18 to “catch up” missed vaccines or to complete the series of three shots.We do not believe there is sufficient evidence to recommend for or against routinely vaccinating women between the ages of 19 and 26, and those women should have an informed discussion with their health care professional about the benefits and risks of the vaccine.

All of this discussion led me to go back to our original guidelines publication.We make every effort to have the best experts participate in our guidelines panels.We do not take funding from industry to support our guidelines efforts, and we do not gain financially from producing our guidelines.I do know that our panel spent countless hours reviewing the evidence, and discussing and debating many aspects of the HPV vaccine before they made their recommendations.

That said, I would be remiss if I didn’t note that a number of the experts on the panel do in fact have industry relationships related to the cervical cancer vaccine.These are, after all, the experts that everyone seeks for their opinions.I know many of them personally and by reputation, and all are highly regarded.But as I noted in last week’s blog on whether or not physicians routinely recommend the vaccine, there are situations where I feel obligated to note potential conflicts, and this is one of those situations.

Ultimately, you will have to make your own decisions and conclusions about what all of this means—especially if you have a daughter who is eligible to receive the vaccine.Far be it from me to tell you what to do, but I do continue to support our guideline recommendation.

There is nothing in these articles that would make me change my mind.Controversy is one thing, but good medicine is another.And many experts I know and trust believe this vaccine continues to be “good medicine.”

The headline on the press release says, “More Than Half of Texas Physicians Do Not Always Recommend HPV Vaccine to Girls.”That sounds bad.

The “sub headline” in the press release says, “Approximately 50 percent do not recommend the vaccine.”That sounds really bad.

The problem is that the headline is misleading and the “sub headline” isn’t true.

When you read the actual research paper, you find out that 75-87% of the doctors are making the right recommendation most of the time.

Given the strong social and political interest in this topic, those differences have significant implications, especially given the headline and sound bite world we live in today.And that could influence how this paper may be used to drive public policy.

First, a bit of background:

We know that the majority of cervical cancers in the United States are caused by two types of human papilloma virus, or HPV.

A cervical cancer vaccine was introduced in the United States in 2006 which could significantly reduce the risk of cervical cancer from these viruses.We also know that the vaccine has not been used as often as was predicted, with somewhere between6% and 25% of 11 to 18 year old girls in this country having been vaccinated to date.We also know that routine vaccination is recommended for 11-12 year old girls by several reputable organizations and federal panels.

The reason for the young age is that the vaccine is not effective once a girl becomes sexually active.Additional recommendations, including those from the American Cancer Society, include offering the vaccine for girls as early as 9 years old, and as a “catch-up” for girls ages 13-18.The Society also recommends a discussion between a woman and her health care professional about cervical cancer vaccination if she is between the ages of 19-26.

The researchers had three primary questions they wanted to answer with their study:

First, they wanted to find out whether or not physicians were recommending cervical cancer vaccination to 11 and 12 year old girls.Second, they wanted to know if physicians would recommend the same vaccine to 11 and 12 year old boys if it became available, understanding that studies have shown the same vaccine now used in girls will also reduce genital infections with HPV in boys.Finally, the researchers wanted to know if physicians agreed that HPV vaccination in 11-12 year old girls should be mandatory.

The study was conducted in Texas, which has an interesting political history with regard to cervical cancer vaccination.Briefly, after the vaccine became available, the Texas governor issued an order that the vaccine would be mandatory in 2007 for girls entering the sixth grade in Texas.However, after strong political protests, the legislature voted to rescind that order.

The researchers conducted an email survey to answer the questions they had posed above.

Focusing on just the physician recommendations to vaccinate 11 and 12 year old girls, the study concluded, “Half of the physicians in this study did not follow current recommendations for universal HPV vaccination of 11-to-12 year-old girls.”

Doesn’t sound too good, does it?

But wait a moment.In a graph in the paper, it says that 75.4 of the doctors “always/usually recommend vaccine to girls” in the primary target population of 11-12 years old. If you look at the same number for girls ages 13-17, the percentage actually climbs to 87.5%.

As a physician who has been in practice, and as someone who is very interested in the need to get doctors to recommend appropriate cancer screening tests to patients, that number actually sounds pretty good.In fact, I think it would be very difficult to get much better than that, especially in the 13-17 year old category.

Essentially, the headline all depends on whether you think there is much practical difference between “always” and “usually.”Frequently, researchers combine those categories into a single number because of the practical implications.Indeed, in their own graphical presentation of the data, the researchers in this paper combined the data.It’s when they wrote the conclusions that they elected to highlight that differences.

And that “sub headline” which says that approximately 50% of the physicians in Texas do not recommend the vaccine should just go away. It is a serious misstatement of the facts in the paper.

Using this information, the authors conclude that “additional efforts are needed to improve clinicians’ awareness of and adherence to national recommendations.”

The study also noted that the most effective way to get these girls vaccinated is to mandate the vaccine.“State vaccination requirements that would ensure high uptake of HPV vaccines also have the potential to narrow existing racial, ethnic, and economic disparities in cervical cancer incidence and mortality…(More than) 40% of Texas physicians in this 2008 study supported mandatory HPV vaccination.”

The authors do point out that there are several barriers to vaccination, including costs and misperceptions of safety and effectiveness—as well as personal parental beliefs—that may impact the rate of vaccination.But they also imply that doctors aren’t doing their job as well as they should.

I simply don’t agree that the data on its face supports that conclusion, and I don’t agree that the data necessarily reflect the opinions and/or practices of physicians across the country.When I dug deeper into the study, I found I had questions about how representative the sample was of all practicing physicians, not to mention questions about how many internists and gynecologists actually treat 11 to 12 year old girls in their practices.I also thought the study was (unintentionally) biased towards younger physicians whose opinions may not reflect the larger (and older) primary care physician workforce.

Some final items:

I want to make it clear that in my opinion this vaccine is useful in preventing cervical cancer.I have no personal opinion (nor does the American Cancer Society) as to whether or not the vaccine should be mandatory.The Society does recommend routine vaccination of girls 11-12 years old.

As I mentioned to a reporter during an interview yesterday, I believe that readers of this blog should be aware of potential conflicts of interest when I write about particular research reports.

In this case, one of the senior authors on the paper lists the following conflicts:

She is a co-Principal investigator on an investigator-initiated grant funded by the company that currently is the sole supplier of the cervical cancer vaccine in the United States; serves as a research consultant/collaborator on a research project sponsored by that company; and sits on one of that company’s advisory boards.

I could not find any indication that the company which makes the vaccine directly or indirectly supported this research, or made some type of grant which helped get the study completed.

The key “take away” message for me is that this particular study is a case example of how one can get attention by emphasizing the problem, as opposed to applauding the success.In my personal opinion, it shows how you can tilt the impact of a scientific paper depending on the message you want to send and the headlines (and sub headlines) that you write.

To sum it all up, whether you think this glass is half empty or half full may just depend on your point of view.

Sometime patience pays off.And sometimes patience means you think you have come to the end of the road, only to find that someone has built an extension for the highway.

That’s the outcome from the next study, which reported that the use of a tumor vaccine in patients with a non-Hodgkin lymphoma called follicular lymphoma were found to have longer remissions after chemotherapy if they received the vaccine when compared to patients who received the same treatment but did not get the vaccine.

This research was no flash in the pan.The basic research which led to this study was first reported in a well-known medical journal back in 1999.Ten years later, we have a report that the use of the vaccine in a select group of patients who were able to have their disease successfully treated and remain in remission for at least six months increased the time to progression of 44.2 months, compared to 30.6 months for the patients who also achieved a complete remission for at least six months but did not receive the vaccine.That is over a 14 month improvement.

But this was a very select group of patients.First, they had to have a lymph node large enough to make the vaccine.Then, they had to achieve a complete remission of their disease on chemotherapy.Then, they had to remain in remission for at least six months before the vaccine could be started.

Each of those requirements puts in place another filter that might influence the results of the trial.And, as the author points out, when you look at the entire patient population with this disease, and given the effectiveness of newer for this disease treatments (which became evident during the time this trial was in progress), there in fact is not that much difference in the “real world” results in survival for both groups.

The researchers concluded that the vaccine did work.The side effects were limited, and the vaccine may be useful in treating these patients in practice.But we are now in a different era in the treatment of this disease, so it is basically back to the drawing board to see if the vaccine still helps in the face of newer, more successful drugs for this lymphoma.Discussions with the Food and Drug Administration for drug approval are ongoing.

In discussing the presentation, Dr. Ron Levy from Stanford University School of Medicine made the point that lymphoma cells have unique markers not common to other cells in the body.That is what makes this cancer a disease where a vaccine may be useful.

We now have antibodies against this target, and we have therapies based on these antibodies that are successful in treating follicular lymphoma. We can use that same target to make a vaccine.

Dr. Levy went on to ask several questions in his discussion, including: Is this result a positive result?Could there be a role for active vaccination in patients with this disease?

He noted that this was a small study with 117 vaccinated patients.The chemotherapy was not a “popular” chemotherapy.Not every patient achieved a complete response and others could not maintain a complete response.There were other unanswered questions about that study that, according to Dr. Levy, could have led to unintended biases in the results.Finally, he concurred with the same comment that I noted above, namely that these patients were the “best of the best” in terms of the opportunity for long-term remissions for their cancer after their treatment.

Will vaccination be part of standard treatment?

As noted by Dr. Levy, the world of treating follicular lymphoma has not stood still.The use of rituxumab (Rituxan) has shown a “powerful advantage” in improving the treatment of follicular lymphoma.In order to find out whether this current vaccine has any value in today’s treatment program to improve the outlook for patients with follicular lymphoma, a new trial would have to be done.

Dr. Levy’s conclusions: a “qualified yes” that the trial is a positive result.But there is much more work to do.

Which brings me back to my first comment: After years and years of work, we have a success but it is a qualified one.It demonstrates the concept, but we don’t know if it will make a real difference in the outlook of patients treated with more modern approaches to follicular lymphoma.We still need to travel further along that extended highway.

The results of a clinical trial studying this controversial vaccine were released this afternoon at the annual meeting of the American Urological Association in Chicago, and the news wires are already humming with the news.

Unfortunately, I still don’t have access to the actual abstract and have to rely on a news release from the company that ran the trial, which is not always the most satisfactory way for me to get information.Once I receive the abstract, I may update my comments if there is any significant new information.

According to the press release, 512 men participated in the trial.They were men who had prostate cancer that had progressed and was no longer responding to hormonal manipulation or medications.They were asymptomatic, which does put them in a better risk profile for long term survival, but this was true both for the men who received the vaccine and received a placebo.The study measured the overall survival of the participants.

For the men receiving Provenge, their survival was increased by 4.1 months compared to those who received the placebo (25.8 months vs. 21.7 months).31.7% of the men receiving Provenge were alive at 3 years, compared to 23.0% of the men who received placebo.Side effects were reported to be very modest.

All of these results were statistically significant, which suggests that the results were not due to chance.

Unfortunately—and to me this is the unusual part of the trial--the vaccine did nothing to delay the progression of the disease.Vaccine or no vaccine, the time to progression was the same.Despite no delay in progression of the disease, survival was prolonged.

The treatment of advanced prostate cancer hasn’t made much progress in the past many years.There are some chemotherapy drugs that help, but they have significant side effects and don’t do much to improve survival.There aren’t many other alternatives out there—such as targeted therapy—that have received much notice for effectiveness in treating this very difficult-to-treat disease.

But we also have to remember that for several cancers the progress in treating the disease over the past 30 or 40 years hasn’t come in one big jump, but rather is the incremental advance of a couple of months here with one drug, and with another couple of months there with another drug.

Provenge has now broken through that barrier, and suggests that we may in fact be able to stimulate our body’s own defense mechanisms to aid our fight against cancer.This in itself is a truly remarkable accomplishment.

In the midst of this promise, I would be less than honest if I didn’t say that there are still some potential pitfalls.

First, as I mentioned a couple of weeks ago, this is a “top line” analysis of the results.A more detailed analysis and publication of the results—not to mention review by the FDA—still must be done.

There has been some background “noise” suggesting that there may be something about the way the men on the placebo arm were treated that may have influenced their survival adversely.Although this is unlikely—and difficult to prove—there is some chatter to that effect.That’s why the review of the data is so important.

The support for that concern can be found in the fact that the vaccine did nothing to delay progression of the disease.Usually, the situation is the other way around: the new drug delays progression of the disease, but may not increase survival.The normal way we think suggests that delay of progression is necessary before you see a survival benefit.That did not happen with Provenge.So, did the men who receive the placebo have something happen to them that may have shortened their lives compared to those who received Provenge?It isn’t likely, but it is possible.

That also leaves open to question whether or not the quality of life of the men who had their lives extended was also improved by the vaccine.Sometimes clinical trials measure quality of life (such as appetite, weight loss/gain, bone pain, ability to function, among others), sometimes they don’t.I don’t know whether or not quality of life was looked at in this trial.But it isn’t much of a life that is extended in intense pain, poor appetite, and wasting away.

All of these thoughts are speculation on my part, but offered in an effort to look beyond the headlines into the questions that will be asked by others as the data is reviewed.

The sooner we can see all of the data from the study, the sooner we can move forward with getting this drug to men who need it if it indeed meets the expectations that have been set with the release of today’s results.

Another day, another announcement of a potentially promising new cancer treatment, and another day of caution. Dendreon is the name of the company that issued the press release and has worked for years to develop the vaccine to treat advanced, hormone-refractory prostate cancer.

In today’s announcement, the company said that the vaccine—called Provenge--“met its primary endpoint of improving overall survival compared to a placebo control.The magnitude of the survival difference observed in the intent to treat population resulted in the study successfully achieving the pre-specified level of statistical significance defined in the study’s design.The safety profile of Provenge appeared to be consistent with prior trials.”

But not everyone is ready—just yet—to say the battle is won.And the advocacy community is poised and ready to fight back if anyone suggests we not accept today’s announcement as the final word as to whether or not this vaccine is effective.

“It certainly sounds good, but we really need to see the details…I will be watching with interest and some hope…Surprisingly, some companies often lack the expertise to fully analyze these trials appropriately,” (Brawley) says.

Within minutes after the story was posted, we started to receive emails criticizing our “wait and see” approach to the news.And we weren’t alone.Posts on the Forbes website claimed the author of the article was inappropriately downplaying the results of the study as well.The suggested “payback”?The author should get prostate cancer and be denied Provenge as a treatment.

The announcement from Dendreon is certainly hopeful news for the men in this country who have advanced prostate cancer.However, until the data is carefully reviewed we won’t know for certain how successful the drug really was in producing a meaningful response in what to date has been a very difficult cancer to treat when it spreads through the body.

Advanced prostate cancer is truly a disease in need of a treatment breakthrough.The American Cancer Society expected in 2008 that about 186,000 men would be diagnosed with prostate cancer, and 28,660 men would die from the disease (data for 2009 projections is still not available).The good news is that the frequency of new cases and deaths from prostate cancer have been declining in this country.

But for men who either diagnosed after the disease has spread, or who recur after primary treatment with surgery or radiation therapy, the outlook is grim.Hormonal manipulation usually works for a period of time, but is not without side effects that negatively impact the quality of life.And for men who have more aggressive disease that escapes from the hormone treatments, there is little to offer in terms of truly effective chemotherapy.Advanced prostate cancer can linger for a long time, and frequently causes severe symptoms with pain being a frequent and severe problem.

So any new treatment that might improve survival and quality of life for men with advanced prostate cancer would be truly welcomed.

We won’t have any real information to look at until the data from the clinical trial is presented at a national urology conference on April 28.Certainly many eyes and ears will be focused on that presentation, not the least of which will be members of the investment community.Even then, the presentation will offer only a snapshot into the effectiveness of Provenge.

As I write this, we don’t know exactly what the data will show.The company is prohibited from releasing that information to anyone prior to the presentation. But we do have a glimpse as to what we might expect, based on a conference call the company held with investment analysts earlier today.

Here is a snapshot of the call:

First, the company would go no further with the details of the data except for what they put in the press release.They did mention that their report today was “top line” and that further analysis of the trial information was necessary.

The CEO of the company, Dr. Mitchell Gold, went on to say that the results of the trial were “unambiguous”, and that the trial clearly hit is target endpoint.When pressed to define that endpoint, Dr. Gold declined to provide more information, citing the need to hold back any further comments pending the presentation in two weeks.

Dr. Gold also mentioned that the median survival in the trial was consistent with other studies of Provenge, and that the vaccine clearly prolonged the overall survival of the patients who either received the vaccine or were supposed to receive the vaccine (called an “intention to treat” analysis, which is appropriate).He also mentioned that some patients who were in the placebo group did cross-over at a later date to receive another formulation of the vaccine.These patients remained in the placebo group as part of the analysis reported today, which means it was even more difficult for a difference to be noted in favor of the vaccine in the treated group if the vaccine had any positive benefit.

Dr. Gold emphasized repeatedly during the call that the analysis was only “top line” and that the company has not had a lot of time to examine the data.Nonetheless, in response to several questions, he indicated that the company is planning on resubmitting an approval application to the FDA in the latter part of 2009, and is already examining ways to initiate marketing and manufacturing for Provenge.

There were several comments during the call stating that the results of the current trial support improved survival for men with advanced prostate cancer who received the vaccine as seen in prior Provenge phase III clinical trials of the vaccine.

The company is clearly enthusiastic about the results.Those of us without access to the information still don’t have as clear a picture as we would like, and we look forward to the actual presentation in late April.

In a phase III trial reported in the Journal of Clinical Oncology in July 2006, researchers reported a 4.5 month increase in median survival (25.9 months for men treated with the vaccine, compared to 21.4 months for men who received a placebo instead).However, in that same study, the vaccine did not improve the time-to-progression for men who received the vaccine (11.7 weeks for vaccine vs. 10 weeks for placebo).

For whatever reason, in that particular trial, it appeared that the vaccine had little effect on one important measure (time to progression)—which actually occurred fairly quickly in a matter of about 3 months—compared to the survival advantage, which took almost 2 years to become evident.

I don’t know if the current trial measured quality of life for the men who received the vaccine, but given the fact that advanced prostate cancer frequently attacks the bone and can cause significant pain, I hope that the vaccine—if in fact it is shown to be truly effective—can do something to control the symptoms of advanced prostate cancer.Simply stated, if the disease progresses quickly with or without the vaccine, living an extra 4 months in agony may be worthwhile to some men, but may not be worthwhile to others.

So, the bottom line is that we anxiously await the presentation of the data and a more detailed review which will hopefully follow in the near future.

We hope the response to the vaccine is a meaningful one, in terms of days of life and the quality of life.And we hope that this vaccine will in fact demonstrate once and for all that we are in fact able to effectively use a vaccine to “wake up” our bodies own natural defense mechanisms to treat a notoriously difficult disease.

If this vaccine does meet those goals, this will be a major step forward on several fronts. Unfortunately, we have learned time and again that however glowing the press reports, until “the data is in”, we won’t know for sure.

Cancer is projected to become the leading cause of death worldwide in 2010.

That is a staggering piece of information and one that deserves our full attention.It means that despite the progress we have made here in the United States and other developed countries in decreasing the burden from cancer, the rest of the world is far behind and is suffering the consequences.

In the last 30 years of the 20th century, the global burden of cancer has more than doubled.That trend is projected to continue, and by 2030 there could be 27 million newly diagnosed cases of cancer, 17 million deaths each year and 75 million people alive with cancer within five years of diagnosis.

Why are we seeing this explosion in cancer?

One quarter of cancers in cancers in developing countries are attributable to infectious diseases, some of which are preventable with currently available vaccines.More importantly, although 12% of cancers in developing countries today are related to tobacco, that number is expected to increase significantly as cigarettes spread their scourge around the world. There are many countries that are still in the relatively early stages of their own tobacco pandemics, and have yet to be impacted to the degree seen in the United States.The future devastation from tobacco on the health of those countries is absolutely frightening.

Another sad tale is that many developing countries are adopting Western lifestyles at a quickening pace.We are exporting our diets, our habits and our fast-food outlets throughout the world.Along with that comes overweight and obesity, and with that an increase in the risk of cancer deaths in both men and women.

Couple these factors with an increase in global population and aging of that population, and you have a formula guaranteed to increase the numbers of people diagnosed and dying from cancer.

The organizations coming together here today have issued a “call to action” that they believe will help stem the tide of this developing tsunami:

1) Make vaccines that prevent infections which cause cancer more widely available to low-income nations.

This is especially needed for cervical cancer, which is a leading cause of cancer death among women in low-income nations.Unfortunately, this vaccine is expensive, and we need to find ways to make it more affordable so women in developing countries can have access.

2) Commit to a comprehensive tobacco control approach in the United States.

We are making progress, but we could do better.The recently released “Report to the Nation” highlighted the wide disparities among states when it comes to effective tobacco control measures.The natural result is that there are parts of this country—including many in the Southeast—where deaths from tobacco-related cancers far exceed those in other parts of the country.This is not a distinction we should be proud of.

161 countries throughout the world have ratified this treaty which is designed to reduce the devastating health and economic burdens of tobacco.Why not us?

4) Support Non-Governmental Organizations’ (NGOs) efforts to build advocacy and resources, empower survivors, and reduce suffering throughout the world.

We have learned here in the United States and elsewhere that power comes from within.We need to take the lessons we have learned, and help others to help themselves in a manner consistent with their own cultures.We need to encourage governments and companies throughout the world to recognize that they have the ability to influence the cancer burden in their own countries.They are far from powerless if they decide to address the issues.

People throughout the world can get the message, and they can do something to help control their fate.We have believed, and we have accomplished.So can people everywhere, through advocacy and raising awareness among the public, governments, civil society and the private sector.

6) Invest in cancer research and expand access to prevention and early detection measures.

Infrastructure is a “hot topic” these days.There is a cancer research infrastructure as well, and that infrastructure is at risk of decaying because of research funding that has been flat or cut.We also need to make certain that every person in this country has access to prevention, early detection and effective treatment for cancer.Now is the time to make certain that everyone can get access to what we already know works.The impact would be astounding.

So, as we gather here in Atlanta this morning, the message will be one of alarm and concern.But it will also be one of hope.

We have accomplished a great deal in this country attacking the burden of cancer.We could do much more.We can also work with our colleagues around the globe to empower people and nations to understand that they too can do more.

They can do more to prevent cancer, especially through controlling the tobacco epidemic before it grips their nations.They can do more to get cancer-preventing vaccines to their people who are suffering the impact of cancers that we in the United States and other developed nations have done much to prevent and control.And they can get the attention of their governments and their corporations in this increasingly flattening world to pay attention to the human “bottom line” as well as the financial bottom line.

Let’s hope that the power of these very special and committed organizations coming together in recognition of this global epidemic is the start of a special journey that we will look back on with pride in the years to come.

There is something that fascinates the public about the possibility of treating cancer with a vaccine.Perhaps that explains why so many abstracts and journal articles about the latest cancer vaccine research find their way into our newspapers, magazines and television reports.

Unfortunately, the study points out—yet once again—that we may be hopeful that cancer vaccines will work, but we are a long way from success.

What is even more startling about this report—aside from the fact that a journal is actually publishing what we call a “negative” clinical trial—is the editorial which discusses the results.The author of the editorial made some not-so- kind comments about how vaccine companies distort reports of vaccine trials, and how investigators make inappropriate claims regarding their research.

The design of the study was straightforward.The researchers randomly assigned otherwise healthy patients who had newly diagnosed kidney cancers that were confined to the kidney to either receive a vaccine made from their tumor tissue or not receive this vaccine.

The vaccine—which was made from something called a “heat shock protein”—was prepared in the lab from cancer tissue removed at the time of surgery.The study was international, with participants coming from several parts of the world, including the United States, Russia, Poland, Israel and Western Europe.

After the vaccine was prepared, it was then shipped back to the doctors caring for the patients and given initially once a week for 4 weeks, then every other week until the vaccine supply ran out.Both groups of patients—half of whom received the vaccine and half who did not—were followed until there was evidence that their cancer returned.

Unfortunately, as pointed out in the journal article and the editorial, there were a number of technical problems with the study.This meant that there were fewer patients to analyze for the final report.Ultimately, there were about 360 patients in each group.

The results of the study showed that there was no evidence that this vaccine made a significant difference in the time to recurrence for these kidney cancer patients.Both patients who received the vaccination and those who did not recurred at similar intervals.There was a suggestion that patients with earlier stage disease did do better than similar patients in the untreated group, but the differences were not large enough to say that the vaccine was responsible for that difference.

Then the authors did something that is not uncommon in vaccine studies.They did an analysis that was not originally planned as part of the initial study design.This is what the authors and others call a “post-hoc analysis.”

These types of analyses are generally frowned upon.Experience has taught us that these not infrequently can lead to erroneous conclusions.Most researchers have come to the conclusion that you plan your study in advance and you determine what outcomes you want to look at when your study is completed.That approach is generally accepted as removing much of the bias that could otherwise result by changing the rules as you go along during the clinical trial.

If you do a study and find an unplanned outcome with a subset of patients, then the appropriate thing to do is to run another study and prove your theory.There are several clinical trials going on right now that are outgrowths of such an approach.

In this report, the authors did in fact do one of these unplanned analyses, and reported on their results as part of this paper.They concluded that in patients with “intermediate-risk” kidney cancer the vaccine decreased recurrences compared to control patients who did not receive vaccine.

They concluded that, although their vaccine did not improve the outlook for kidney cancer patients when measured by conventionally accepted approaches, “Nevertheless, the observation that treatment with vitespen (the cancer vaccine) confers an apparent clinical benefit to patients with earlier stage disease with better prognosis is biologically plausible and consistent with a wealth of scientific and clinical evidence.”

In that case, the FDA has decided not to approve the vaccine based on the unplanned analysis, pending the results of additional clinical trials.To say the least, the proponents of Provenge are not pleased.They have lobbied Congress, the FDA and everyone they can think of to get the vaccine approved based on that analysis as opposed to waiting for the completion of the clinical trial.

The editorial which accompanied the kidney cancer article in The Lancet was vehement on these issues.In fact, I don’t recall reading many (if any) editorials that have attacked the conclusions of researchers and the sponsoring pharmaceutical company so directly in a major medical publication.

The editorial, written by James Yang, MD from the National Cancer Institute, pointed out the results and technical failings of the study.He also noted that, just like several other cancer vaccines, there were early phase studies of vitespen that looked promising in the treatment of cancer but didn’t pan out when studied as part of larger clinical trial.

Dr. Yang stated that one of the allures of cancer vaccines is that they don’t have many side effects.“That lack of toxicity also makes it easier to dismiss the fact that only rare objective regressions of metastatic disease were seen…Unfortunately, the results do not support the hypothesis that vitespen is beneficial.”

He goes on to note that cancer vaccines simply don’t have the power to help the body fight the cancer cells, much like they would fight an infection.The theory behind cancer treatment vaccines makes sense, he notes.It is turning that theory into reality that has been so difficult for these past many years.

Then the editorial gets a bit more interesting and less conventional in its statements:

“Yet the credibility of the field of cancer immunotherapy is weakened when some investigators, and particularly vaccine companies, cannot accept the results of randomised trials.There has been extensive use of post-hoc subset analyses to salvage underpowered studies or those that fail to reject the null hypothesis (my note: that means studies that show the vaccines don’t work).Such practices are akin to shooting the arrow first and being permitted to draw the target afterwards…As Wood and co-workers (the authors of the article) state, ‘interpretation of post-hoc analyses must be approached with caution’, which is largely because subsequent prospective studies often cannot verify the results.”

Dr. Yang goes on to chastise the company that has sponsored the research on vitespen for misleading press releases.Those press releases dealt with the announcement that this vaccine will be available to patients in Russia in the second half of 2008.

“One final issue to be raised is the differences seen between results and analyses as presented in peer-reviewed publications and the sometimes selective reporting in company press releases.In a press release on April 8, 2008, and despite the results of the trial reported today, the manufacturer of vitespen highlighted the approval of vitespen in Russia for patients with intermediate-risk renal cell cancer.That announcement uses relative rather than absolute risk and fails to point out that the analysis was not pre-specified in the protocol…

Commercially driven efforts that spin or obfuscate the conclusions of such a trial should be vigorously resisted because such efforts seriously erode its value.”

I have been watching the efforts to develop a vaccine to treat cancer for over 30 years.

I’m sorry if I seem a bit skeptical, but time and time again when these studies are presented to me for comment I have to express my skepticism, and advise that we must wait for the results of larger, more appropriate clinical trials before we can get truly excited about any particular vaccine.

Almost always when I see these early abstracts they are accompanied by glowing comments from an investigator suggesting that their vaccine research is a significant breakthrough, when in fact it is not.These abstracts are frequently accompanied by a similarly glowing press release from a major research university where the research was done which further creates a spin suggesting there is more to the research report than actually exists on careful review.

I know how hard the researchers are working on trying to get this right.And I know how difficult it is for those with cancer to hear media tidbits that this vaccine or that vaccine may help them survive their cancer longer. And I know that the argument is going to be made that the Russians are more forward-thinking in their treatment of kidney cancer, since you can get the vaccine there and not here.

But—just as Dr. Yang so succinctly and directly pointed out—there have been too many promising early reports for cancer treatment vaccines that never panned out when tested in the real life conditions of a large clinical trial.There are more than a few reputations in cancer research and treatment that have been made on the early promises of vaccines, to be deflated after years of work when the theory didn’t result in an effective cancer treatment.

So the journalists will continue reporting on early vaccine studies that appear promising, and I will be quoted urging caution until we see real results in real clinical trials.And patients and their families will continue to be drawn into the cycle of hope and hype that has been so destructive in cancer treatment in years past.

We owe it to everyone to be as objective as possible when we report our research results or issue our press releases.As researchers, we must avoid the allure of overpromising, then under delivering.

Ultimately, what the public needs to know are the facts.Then all of us can focus on making the best decisions and recommendations in caring for our patients

I did something the other day that has bothered me for the past 72 hours: I decided not to publish a comment in my blog because of fear of retribution or possibly retaliation.

Today, I decided to correct that decision and discuss my concerns.

Although it may not be a momentous piece of information, it nonetheless made me think long and hard about why I made the decision I did at that time, and what the implications were for providing information to the public about current controversies in oncology.

What has concerned me were the comments in my draft about an investigational cancer vaccine called Provenge.

As I noted in that blog draft, we live in a different world today than we did years ago when it comes to public knowledge and influence on the drug approval process.

We have more information readily available, with many more people having access to that information.I call this phenomenon the “democratization of information.”

Along with that democratization (if there is such a word) comes the sense among many that they want information provided to them so that they can make up their own minds regarding the validity, value and implications of that information.

It is one thing to have that information about, for example, a presidential candidate or a new car.It is something else, in my personal opinion, when it comes to a new medicine or a new treatment.

I agree with my colleagues that it is important that people have access to the information, but the subtleties of interpretation do require knowledge, training and expertise that are not possessed by most people who have not had training in medicine.

This brings us to the Provenge story.

I will admit that I am not privy to all of the information and primary data related to Provenge, an investigational vaccine being studied in the treatment of men with advanced prostate cancer. Much of what I do know comes from other sources that have reported on this topic.

That said, in a nutshell the story is that several years ago the company that has been working on this vaccine reported that their clinical trial intended to demonstrate that Provenge was useful in the treatment of advanced prostate cancer did not meet its goal.

Subsequently, on reanalysis, they concluded that there was some information in that “failed” trial which suggested that the vaccine may have in fact increased the lifespan of the men who received the vaccine.

The company then supplied the data to the Food and Drug Administration for review and possible approval of the vaccine.

Within the past several weeks there have been several news reports about the developments surrounding the FDA’s analysis and decision.

First, one of the FDA’s outside advisory committees suggested the vaccine be approved, despite some problems with the quality of the statistics that are normally used to determine whether or not in fact a drug (or vaccine, in this case) is effective for the disease in question.

A report in a widely followed cancer newsletter called The Cancer Letter reported that the advisory committee meeting was apparently raucous, with the advocates present in the audience making their opinions known very vocally when someone agreed or disagreed with their position that the vaccine should be approved for general use in the treatment of prostate cancer.

Subsequently, as again reported in the Cancer Letter, some highly respected cancer specialists wrote the FDA regarding their concerns about possible approval of the vaccine.They felt that the data did not support effectiveness, and pointed out that there were ongoing clinical trials that would directly answer these questions, without the statistical problems of the current data.

The FDA decided to not approve the vaccine, and await the results of the ongoing clinical trial.

That apparently led the advocates in favor of vaccine approval to develop a series of actions with the goal of changing the FDA’s mindset.

The advocates had posted an announcement on a website that they were planning a rally for Saturday morning at ASCO. They also planned a rally in Washington yesterday and today to meet with Congress and the FDA.

Their position is that someone who wanted access to Provenge should be able to receive the vaccine.The argument they make is that if it appears the vaccine may be effective, then why should men who are facing a fatal disease be denied the opportunity to receive the vaccine when it may improve their survival?

This is the question that piqued my interest in this topic, and how our standards may be changing when it comes to the decisions we make in caring for our patients.

For years, much of what we did as doctors—in treating ALL types of illnesses—was based as much on tradition and expert opinion as it was on science.Now, as physicians, we are trying to move our care into more of an evidence based model, where we develop the science to back up our actions.

But with the spread of the internet—and the democratization of information—we find patients and others are beginning to influence our treatment choices, much as is the case with DCA and now with Provenge.(Other alternative therapies are also driven by this “word-of-mouth” (or perhaps “word-of-internet” would be a more apt description) phenomenon, and are now very much a part of the landscape of cancer treatment.)

So that is what interested me.I also had expressed in the blog draft my personal opinion that based on what I had read, waiting for the results of the clinical trial was the appropriate thing to do.

We have seen too many examples in cancer medicine and other areas of medical treatment and practice where the initial thoughts have proven wrong—and even harmful—to ignore good science in this particular situation.(The current discussions surrounding the potential harms of erythropoietin come to mind as an example.)

On my way to the ASCO meeting, I heard that the situation may have become even more serious than I had realized.

What made me pull my comments from that draft blog was a message I received that serious personal threats had been made against two physician scientists who had urged the FDA to delay approval of Provenge, pending the results of the clinical trial. And, I was told, these were threats of the most serious type.

Because of the risk, I decided not to say anything publicly.Although I had written my blog on this topic, I edited the comments regarding Provenge out of the final posting which you may have read on Saturday.

For your background, what you see on my blog is generally what I write.I may make some editorial edits, or perhaps tighten up some comments.But I have never removed a “theme” from one of my blogs under pressure—either real or perceived--since I started writing it almost two years ago.

But this time was different.

As I spoke with some reporters who attended ASCO, a common theme emerged.

They, too, had become reluctant to cover the story because of fear of retaliation.One reporter said that in their opinion you had to “steel yourself” if you intended to report an opinion or comment in support of the FDA’s conclusion.

Frankly, this troubles me a great deal.

On Saturday afternoon I decided to give an interview to a major business journal and basically say that this is not the way we should do our science.

What I said was that we may not always agree on the science, but intimidation is not the answer to making evidence-based decisions regarding drug approvals.(As I write this, I don’t know if those comments have been published.)

Then, yesterday, the New York Times went public with confirmation that threats of physical harm had in fact been made against the experts who opposed approval of Provenge.The Times reported that one of the physicians actually had bodyguards with him as he presented at ASCO.

In that interview, the physician indicated his concern that more of his colleagues had not come out publicly to support him in his time of need.I suspect that, like me, many of his colleagues have been intimidated, and are frankly afraid to make a public comment.

As it turned out, the rally on Saturday had a small number of participants and nothing untoward occurred.

There were no meetings invaded, no sessions disrupted, and no one harmed.

As I said above, my personal opinion based on the information I have read is that it is appropriate to await the results of the current clinical trial to determine whether or not in fact Provenge improves survival in advanced prostate cancer before approving the vaccine for general distribution.

The question of access to investigational drugs is an important one, and one that is currently being debated in multiple forums.When it comes to drug (or vaccine) approval, we must have the best evidence possible that the drug is effective, and a valid understanding of what risks may be associated with the drug.

But to threaten established, knowledgeable investigators who honestly express their well-reasoned opinions, which in turn “chills” rational discussion is, from my point of view, simply unacceptable.

We will always be subject to those who try to influence our comments, decisions and recommendations.I personally try to limit those outside influences, and try my best to declare when I perceive there may be a conflict of interest that people should know about when I make a statement in a public forum.

Public debate and discussion is appropriate. Intimidation is not.Disclosure is essential.

Ultimately, I am hopeful that our decisions whether or not a particular drug should be approved will be based on the best evidence available, and the best quality interpretation of that evidence.

Yes, there are problems with the system currently in place.Every human system is subject to personal interpretation and potential error.

That does not mean that those involved in making those decisions and making comments on those decisions are not trying to do the best they can under the circumstances.

Fear and intimidation should not make us hold back the expression of our legitimate scientific concerns.

I know that the perception of potential intimidation influenced me a couple of days ago, and I hope that sharing these thoughts with you will help assuage the nagging guilt that has bothered me since I made that decision.

In the meantime, I hope that those who disagree with my position will be rational—and, non-threatening.

A presentation this afternoon at ASCO’s annual meeting this afternoon in Chicagois going to discuss the effectiveness of an oral targeted therapeutic drug called sorafenib (Nexavar) in the treatment of primary liver cancer.

(We need to distinguish primary liver cancer—which originates in the liver and is known by its medical name hepatocellular carcinoma—from cancers that spread to the liver from other organs, such as breast, lung and colon cancer.)

The report is important because up until now there have been no really effective chemotherapeutic agents to treat this form of cancer.In addition, this treatment is given by mouth, and the side effects were relatively modest.In fact, the same level of side effects occurred both in the patients who took the drug, and those who took a placebo.

The researchers are going to report that the patients who took sorafenib lived a median of 10.7 months, while those who took the placebo (or dummy pill) lived a median of 7.9 months.(Median is a statistical measure that means half of the patients lived longer than a particular time, while half the patients died before that time).

Looked at another way, the patients who took sorafenib took about 5.5 months until their disease showed that it was progressing.Those on the placebo had evidence of disease progression at 2.8 months.

In essence, the drug increased the survival of the typical patients with primary liver cancer about 2.8 months.

That doesn’t sound like much, but it is likely a real finding.In fact, if you understand what median means, some of the patients in this trial probably lived longer than the 10.7 months.

And, if you have read my blog previously, you have seen me write that the history of improvements in the treatment of cancer happen much more often in small increments and not in big “one-time” gains.

This report is also important for some of the other considerations beyond extending life for 2.8 months.

First, if you read the information above correctly, you will note that in this particular international clinical trial, the drug was compared to a placebo.A placebo, more commonly called a “dummy pill” or a “sugar pill” is essentially a pill with no active ingredient and not intended to have a beneficial therapeutic effect.

I am not aware of many clinical trials in cancer that compare a new drug for treating a cancer against a placebo.You just don’t see that happen very often in cancer research these days.

So why a placebo?After all, although liver cancer is less common in the United States, there MUST be a standard treatment to offer.

In fact, for metastatic or recurrent or unresectable primary liver cancer, there IS no standard chemotherapy listed.Nothing at all.

They do recommend clinical trials or best supportive care (that is medical language for making someone comfortable but not actively treating them with chemotherapy or other modalities) if someone can’t be treated with standard methods or has recurrent disease.

So the bottom line is that we don’t have much to offer patients in these circumstances.

That is not to say we don’t have treatments to offer patients with liver cancer.But those treatments are more surgically oriented such as surgically removing the cancer when possible, or even transplanting the liver in a patient with liver cancer who meets certain criteria.

There are other techniques as well where doctors can “ablate” the cancer by using freezing techniques, microwave or what is called radiofrequency ablation, for example.

Liver cancer is becoming more common in the United States with 19,160 new cases expected to be diagnosed in the United States according to the American Cancer Society’s Cancer Facts and Figures 2007.The large majority of patients with this cancer are men, and in 2007 we estimate that 16,780 people in this country will die from this disease.

This is, according to one of my colleagues, one of the cancers that is increasing most rapidly in the United States in men.

This is a cancer that is known to primarily be caused by infection with Hepatitis B and Hepatitis C.

Fortunately, in this country, we have a decreasing incidence of hepatitis, in no small part because we are able to offer immunization against hepatitis B to our children.We have also significantly improved our ability to test blood transfusions for these viruses, which used to be a significant means of transmission on this virus.

But we also must keep in mind that primary liver cancer is a significant world-wide health risk, in no small part due to the fact that immunization is not widely practiced, and personal and medical hygiene habits are much worse in many developing countries than they are here in the United States.

In 2005, it was estimated there would be 667,000 cases of primary liver cancer throughout the world, making liver cancer the 6th most common cancer in the world.It is the 18th most common cancer in the United States.

83% of the new cases of liver cancer occur in developing countries., but in the United States the incidence of liver cancer has been occurring for the past 20 years.

In the developing countries, 37% of the new cases of liver cancer are attributable to hepatitis B infection, 25% to hepatitis C, and 10% to liver fluke infections.

Sharing of needles, poor personal hygiene and direct person-to-person transmission account for many of the hepatitis B and hepatitis C infections.

In the United States, we are able to offer treatment for chronic hepatitis infections, but we don’t know how much of an impact this has on the transformation to liver cancer.In the developing world, these types of treatments are far less available.

So what does all of this mean?

We are fortunate to have a new drug that is clearly effective—albeit modestly—in the treatment of this previously untreatable disease.That offers some hope, but more importantly signals the opportunities for real advances in the treatment of primary liver cancer.

We also need to understand this is a disease that, although certainly of concern in the United States, is a major health threat throughout the world especially in developing countries.

Liver cancer is a disease that would occur less frequently if we had an effective international immunization strategy and an educational strategy focused on good health and hygiene behaviors and improvements in medical care delivery systems (such as avoiding the reuse of needles in medical settings).

But this is difficult to accomplish, and many barriers are in place which prevent the adoption of these simple, inexpensive and effective approaches to reducing these infections and in turn reducing the incidence of primary liver cancer.

How we are going to be able to get the benefits of this new drug to developing countries where it is most needed remains the unanswerable question.This drug is expensive, and probably far beyond the means of those who need it most.

And that raises the larger issue that I have discussed previously, namely how are we going to be able to afford our miracles.

We need to develop a sustainable economic/business model that works for everyone: the companies that discover, market and manufacture these drugs; the insurers and governments who pay for the drugs; and, most importantly, the patients who need the drugs.

Finding a solution to that conundrum is, in my personal opinion, probably one of the most important issues we face in cancer treatment today.